Method for increasing throughput in an automatic clinical analyzer by duplicating reagent resources

ABSTRACT

A method for maximizing analyzer throughput irregardless of the mix in demand of different assays to be conducted by duplicating the reagents required to conduct selected assays in at least two separate reagent servers and also enabling newly incoming selected assays to be conducted using reagents from whichever reagent server has the smaller backlog of such high-volume assays.

FIELD OF THE INVENTION

The present invention relates to a method and apparatus forautomatically processing a patient's biological fluids such as urine,blood serum, plasma, cerebrospinal fluid and the like. In particular,the present invention provides an improved method to increase thethroughput of patient samples in a clinical analyzer adapted to performa number of different clinical assays.

BACKGROUND OF THE INVENTION

Various types of tests related to patient diagnosis and therapy can beperformed by analysis assays of a sample of a patient's infections,bodily fluids or abscesses. Such patient samples are typically placed insample vials, extracted from the vials, combined with various reagentsin special reaction cuvettes or tubes, frequently incubated, andanalyzed to aid in treatment of the patient. In typical clinicalchemical analyses, one or two assay reagents are added at separate timesto a liquid sample, the sample-reagent combination is mixed andincubated within a reaction cuvettes. Analytical measurements using abeam of interrogating radiation interacting with the sample-reagentcombination, for example turbidimetric or fluorometric or absorptionreadings or the like, are made to ascertain end-point or rate valuesfrom which an amount of analyte may be determined using well-knowncalibration techniques.

Although automated analyzers for chemical, immunochemical and biologicaltesting of samples are available, analytical clinical technology ischallenged by increasing needs for improved levels of analysis. Inaddition, due to increasing pressures on clinical laboratories to reducecost-per-reportable result, there continues to be a need forimprovements in the overall cost effectiveness of clinical analyzers. Inparticular, sample analysis may be more effective by increasing assaythroughput thereby reducing the cost thereof.

An important contributor to maintaining high assay throughput ofautomatic analyzers is the ability to quickly process a plurality ofsamples through a variety of different assay process and signalmeasurement steps. If no premium was placed on space within health carefacilities, clinical analyzers could be designed for high-speedthroughput by simply spacing apart multiple numbers of rugged componentsin dedicated positions to carry out different assay technologies. Thisis not feasible and even further, there are different standards forevaluating the rate of throughput of a clinical analyzer. A volumethroughput measurement relates to how much time is required for allassays on all samples to be tested to be completed. Alternately, anassay throughput measurement may relate to how much time is required fora specified assay of a specified sample to be completed. For example, interms of volume throughput, 1000 patient samples may be completed during4 hours but the first result may be available only 3 hours afterstart-up. However, in terms of assay throughput, a first assay resultmay be available 30 minutes after a sample is placed on an analyzer butthe last result may be available only 10 hours after start-up. Suchdiverse values in analyzer throughput are not generally acceptable tolaboratory personnel and therefore automatic analyzers are required tosimultaneously have a high volume processing throughput in terms ofsample assays/hour as well as a fast turn-around time to the firstavailable reportable result.

One common method of scheduling assay resources to maximize throughputis based upon the use of a predetermined fixed cycle where all assayresources in the instrument operate within a fixed length, predeterminedcycle. Systems having this scheduling method have each assay resourcereturning to a predetermined location at the end of each cycle.Automated analyzers which use a predetermined fixed cycle method ofscheduling the timing of resources also have single chronologyoperation. Each container of sample proceeds through each of theoperational stations of the analyzer in the same order. The Stratus® IIImmunoassay System is such an automated immunoassay system and isdescribed in Volume 41 of the J. Clin. Immun. In the Stratus analyzer, agenerally circular reaction carousel moves forward a fixed distance foreach cycle of the system, indexing sequentially in a clockwise fashionpast an incubation stage, a washing stage and a reading stage. A similarprocess is described in U.S. Pat. No. 5,575,976 in which each assayresource has a predetermined fixed operation window within the fixedprocessing cycle. Consequently, the control for one assay resource canrely on predetermined timing of other dependent and independent assayresources. Therefore, analyte tests having variable protocols and thatare processed by moving reaction vessels in different chronologies canbe interleaved if their assay resource requirements do not conflict,i.e., analyte tests with shorter processing time can be entered afterthose with longer processing times and the shorter analyte test canfinish first. This can be achieved because the means of transportingreaction vessels containing assay constituents can present reactionvessels to the necessary assay resources in whatever order is required,regardless of entry order.

U.S. Pat. No. 5,434,083 uses a rotating reaction vessel train in whichan analysis time of each of the test items is set to correspond to thenumber of times of circulation (number of cycles) of the reactionvessels on the reaction line. A reaction vessel renew device isselectively controlled for each reaction vessel in accordance with thenumber of cycles. Thus, a test item which requires a short reaction timeis processed in a smaller number of cycles of the reaction line and atest item which requires a long reaction time is processed in a largernumber of cycles The analyzer can sequentially process a plurality oftest items which require different reaction times for one sample.

U.S. Pat. No. 5,482,861 operates an automated continuous and randomaccess analytical system capable of simultaneously effecting multipleassays of a plurality of liquid samples wherein scheduling of variousassays of the plurality of liquid samples is followed by creating a unitdose and separately transferring a first liquid sample and reagents to areaction vessel without initiation of an assay reaction sequence,followed by physical transfer of the unit dose disposable to aprocessing workstation, whereby a mixture of the unit dose disposablereagents and sample are achieved during incubation.

U.S. Pat. No. 5,576,215 operates a biological analyzer whereininstrument systems used to perform assays of the biological samplesloaded into the analyzer are operated in accordance with a scheduledeveloped by a scheduler routine. The scheduler routine determinesinterval periods between operations performed by the analyzer instrumentsystems on each biological sample as a function of an entered load listunless a fixed interval period between the operations is required andschedules instrument system operations and the determined intervalperiods. The biological system analyzer performs assays of thebiological samples by operating the analyzer instrument systems inaccordance with the developed schedule.

U.S. Pat. No. 5,679,309 discloses a method for controlling an analyzerincluding a rotatable, circular reaction carousel which hascircumferentially spaced cuvettes. Each cuvette, according to the menuof the analyzer, is designated to receive a selected reagent and aselected sample for reaction and analysis and, post-analysis, be washedfor re-use. A drive indexes the reaction carousel to position thecuvettes according to the menu and in proper sequence, for receipt ofreagent, sample and for wash and for analysis. When photometric analysisis used, the drive operates on a sequence of a spin cycle, during whichthe reaction carousel is spun for photometric analysis of reactingcuvettes, and a park cycle, for a period of time for insertion ofreactant, sample and/or for wash.

U.S. Pat. No. 5,846,491 increases throughput by employing an analyzercontrol system with means for allocating assay resources to one of anumber of reaction vessels as a function of the time cycle for thatvessel and transferring reaction vessels directly from one assayresource station to another according to a chronology selected from aplurality of different predetermined chronologies.

U.S. Pat. No. 5,985,672 also addresses the need for high-speedprocessing by employing a pre-processor for use in performingimmunoassays on samples for analytes in the sample employingconcentrically positioned incubating and processing carousels. A singletransfer station permits reaction vessels containing sample and reagentsto be moved between the carousels. The samples are separated, washed andmixed on the processing carousel and incubated on the incubatingcarousel thus speeding up processing throughput.

Another scheduling method used in automated analyzers does not use afixed cycle, instead using a scheduling method referred to as “kitting.”U.S. Pat. No. 6,096,561 discloses an automated continuous and randomaccess analytical system, capable of simultaneously effecting multipleassays of a plurality of liquid samples wherein various assays arescheduled for a plurality of liquid samples. Through kitting, the systemis capable of creating a unit dose by separately transferring liquidsample and reagents to a reaction vessel without initiation of an assayreaction sequence. From the kitting means, multiple, kitted unit dosedisposables are transferred to a process area, where an aliquot is mixedfor each independent sample with one or more liquid reagents atdifferent times in a reaction vessel to form independent reactionmixtures. Independent scheduling of kitting and mixing is achievedduring incubation of the multiple reaction mixtures, simultaneously andindependently. The system is capable of performing more than onescheduled assay in any order in which a plurality of scheduled assays ispresented. The incubated reaction mixtures are analyzed independentlyand individually by at least two assay procedures which are previouslyscheduled.

From this discussion of the art state in automated clinical analyzers,it may be seen that while considerable progress has been made towardincreasing analyzer throughput, there remains an unmet need for a systemand apparatus that provides a high volume throughput for different typesof assays, particularly in view of the fact that throughput fordifferent peak load times within a health care facility can varydepending on what assays are requested to be performed and how thoseassays are performed on an analyzer. In particular, assay demandpatterns for early morning patient samples are usually found to bedifferent from assay demand patterns for mid-day samples and littleattention has been given as to how this disparity in assay demandpatterns may be advantageously addressed.

SUMMARY OF THE INVENTION

Clinical analyzers typically include an assay reaction carousel forholding reaction cuvettes which is rotated in stepwise movements in aconstant circular direction, the stepwise movements separated bystationary dwell times, during which dwell time an assay operationaldevice may perform different operation on an assay mixture containedwithin the reaction cuvette. An analyzer on which the present inventionmay be performed has at least two separate reagent servers orinventories of reagents as well as a plurality of conventional assayoperation stations, such as sensors, reagent add stations, mixingstations, separation stations, and the like. The objective of maximizinganalyzer throughput regardless of the mix of different assays to beconducted is difficult to achieve because health care facilitiestypically experience a first demand pattern at the beginning of a dayand a different second demand pattern towards the middle of a day. Dueto the practicality of performing routine assays on new patient samplesmost often beginning early in a day, a larger percentage of high volume“routine morning” assays are performed by the analyzer at the beginningof a day in contrast to a larger percentage of lower volume “esotericafternoon” assays being requested later in the day. This difference indemand patterns may be explained in that after a series of “routinemorning” assays have been analyzed by a physician, the resultsfrequently indicate the need for additional diagnostic testing andtherefore “esoteric afternoon” assays are ordered. The principal objectof the present invention is to provide a method for using an automaticclinical analyzer in a manner that achieves a maximum high throughputirregardless of the different assay demand patterns required to beperformed by the analyzer at different times of a day. This inventionachieves its stated object by duplicating the reagents required toconduct at least one high-volume assay in at least two separate reagentservers so as to increase throughput regardless of whether the incomingassay demand pattern has a larger percentage of a first group of assays( e. g., high volume “routine morning” assays) or a larger percentage ofa second group of different assays ( e. g., lower volume “esotericafternoon” assays). In addition, the present invention enables newlyincoming high-volume assays to be conducted using reagents fromwhichever of at least two reagent servers has the smaller backlog ofassays.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be more fully understood from the following detaileddescription thereof taken in connection with the accompanying drawingswhich form a part of this application and in which:

FIG. 1 is a schematic plan view of an automated analyzer in which thepresent invention may be practiced;

FIG. 2 is a simplified plan view of a portion of the analyzer of FIG. 1;

FIG. 3 is a perspective elevation view of an automated aliquot vesselarray storage and handling unit of the analyzer of FIG. 1;

FIG. 4 is perspective elevation view of an aliquot vessel array usefulin the analyzer of FIG. 1;

FIG. 5 is a perspective view of a reaction container useful in theanalyzer of FIG. 1;

FIG. 5A is a perspective view of a vial carrier useful in the analyzerof FIG. 1;

FIG. 6 is a top plan view of a random-access reagent containermanagement system useful in the analyzer of FIG. 1;

FIG. 7 is a chart showing the time sequence for various operationalevents performed for different types of assays conducted by the analyzerof FIG. 1;

FIG. 8 illustrates a typical rate of incoming patient samples havingassays to be conducted over a full 24-hour day within a clinic;

FIG. 9 illustrates a non-optimized partitioning of assays and reagentsservers on the analyzer of FIG. 1; and,

FIG. 9A illustrates an optimized partitioning of assays and reagentsservers on the analyzer of FIG. 1 in accord with the present invention.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1, taken with a simplified FIG. 2, shows schematically the elementsof an automatic chemical analyzer 10 in which the present invention maybe advantageously practiced, analyzer 10 comprising a reaction carousel12 supporting an outer cuvette carousel 14 having cuvette ports 20formed therein and an inner cuvette carousel 16 having vessel ports 22formed therein, the outer cuvette carousel 14 and inner cuvette carousel16 being separated by a open groove 18. Cuvette ports 20 are adapted toreceive a plurality of reaction cuvettes 24 that contain variousreagents and sample liquids for conventional clinical and immunoassayassays while vessel ports 22 are adapted to receive a plurality ofreaction vessels 25 that contain specialized reagents for ultra-highsensitivity luminescent immunoassays. Reaction carousel 12 is rotatableusing stepwise movements in a constant direction, the stepwise movementsbeing separated by a constant dwell time during which carousel 12 ismaintained stationary and computer controlled assay operational devices13, such as sensors, reagent add stations, mixing stations and the like,operate as needed to perform the myriad of operations required toperform clinical assays on an assay mixture contained within a cuvette24. Such devices and their operational control by a conventionalmicroprocessor based computer 15 are well known in the art and need notbe described herein.

An indexing drive for the reaction carousel 12 moves the reactioncuvettes in the constant direction a predetermined numbers ofincremental steps. The length of the circumference of cuvette carousels14 and 16, the separation distance between cuvette ports 20 and 21 andalso between ports 22, the number of cuvette ports 20, 21 and 22, andthe number of increments per indexing are selected so that any givencuvette port 20, 21 or 22 returns to its original starting positionafter a fixed number of incremental steps. Thus, all cuvette ports 20,21 and 22 on the reaction carousel 12 return to their original locationin a full operational cycle time, hereinafter identified as “CT”, whichis determined by the fixed number of incremental steps multiplied by thesum of dwell time at each assay device and the time required for astepwise movement. This predetermined movement cycle facilitates theprecise tracking by computer 15 of each and every cuvette port 20, 21and 22 and reaction cuvettes 24 contained therein, including havinghistorical data concerning the types of assays conducted in each andevery reaction cuvette 24.

FIG. 2 further illustrates a layout of carousel 12 in which ports 22,marked “C” are dedicated exclusively to the use of Type C assays,described hereinafter, and are equally spaced along the circumference ofcuvette circle 16 in radial alignment with alternate cuvette ports 20equally spaced along the circumference of cuvette circle 14. Incontrast, cuvette ports 20 and 21 are useful for Type C assays as wellas Type B and Type A assays, also described hereinafter. In anadvantageous embodiment, every other cuvette port 20 is dedicatedexclusively to the use of Type C assays, also marked “C”, and theintervening alternate cuvette ports 21 are dedicated to the use of TypeB, marked “B”, and Type A assays. For the purpose of illustration, asingle cuvette port 21 is marked “B/A” to indicate that a certain port21 may be initially used to therein perform a certain Type B assay andafter that certain Type B assay is completed, that certain port 21 maybe subsequently used to therein perform a certain Type A assay during asingle full operational cycle time CT.

Analyzer 10 is controlled by software executed by the computer 15 basedon computer programs written in a machine language like that used on theDimension® clinical chemistry analyzer sold by Dade Behring Inc, ofDeerfield, Ill., and widely used by those skilled in the art ofcomputer-based electromechanical control programming. Computer 15 alsoexecutes application software programs for performing assays conductedby various analyzing stations 17 within analyzer 10. Analyzing stations17 may be located proximate outer reaction carousel 12 and are adaptedto measure light absorbence in or emission from cuvettes 24 at variouswavelengths, from which the presence of analyte in the sample liquid maybe determined using well-known analytical techniques. Stations 17typically comprise conventional photometric, fluorometric or luminescentmeasuring devices adapted to perform an interrogating measurement at anyconvenient time interval during which reaction carousel 12 isstationary.

Temperature-controlled reagent storage areas 26, 27 and 28 store aplurality of multi-compartment elongate reagent cartridges 30 like thatillustrated in FIG. 5 and described in co-pending application Ser. No.09/949,132 assigned to the assignee of the present invention, or vialcarriers 30A seen in FIG. 5A, and containing reagents in wells 32 asnecessary to perform a given assay. A lock-out device 31 is provided toprevent accidental re-use of a previously used reagent container 30. Asdescribed later, reagent storage area 26 comprises a first reagentoperation carousel 26A, from which reagent cartridges 30 may be movedfor reagent preparation operations like hydration and remix, and asecond reagent operation carousel 26B, in which reagent cartridges 30are inventoried for access by a reagent aspiration and dispense arms 60.FIG. 1 shows an embodiment in which first reagent operation carousel 26Aand second reagent operation carousel 26B are circular and concentric,the first reagent operation carousel 26A being inwards of the secondreagent operation carousel 26B. Reagent containers 30 or reagent vialcarrier 30A may be loaded by an operator by placing such containers 30or carriers 30A into a loading tray 29 adapted to automaticallytranslate containers 30 or carriers 30A to a shuttling positiondescribed later. Reagent vial carriers 30A contain solutions of knownanalyte concentrations in vials 30V and are used in calibration andquality control procedures by analyzer 10.

A bi-directional incoming and outgoing sample tube transport system 36having input lane 34A and output lane 34B transports incoming individualsample tubes 40 containing liquid specimens to be tested and mounted insample tube racks 42 into the sampling arc of a liquid sampling arm 44.Liquid specimens contained in sample tubes 40 are identified by readingbar coded indicia placed thereon using a conventional bar code reader todetermine, among other items, a patient's identity, the tests to beperformed, if a sample aliquot is to be retained within analyzer 10 andif so, for what period of time. It is also common practice to place barcoded indicia on sample tube racks 42 and employ a large number of barcode readers installed throughout analyzer 10 to ascertain, control andtrack the location of sample tubes 40 and sample tube racks 42. Suchreader devices and the techniques for tracking are well known in the artand are not shown in FIG.1 nor discussed further.

Sampling arm 44 supports a liquid sampling probe 46 mounted to arotatable shaft 48 so that movement of sampling arm 44 describes an arcintersecting the sample tube transport system 36 and an aliquot vesselarray transport system 50, as seen in FIG. 3. Sampling arm 44 isoperable to aspirate liquid sample from sample tubes 40 and to dispensean aliquot sample into one or more of a plurality of vessels or wells52W in aliquot vessel array 52, as seen in FIG. 4, depending on thequantity of sample required to perform the requisite assays and toprovide for a sample aliquot to be retained by analyzer 10 withinenvironmental chamber 38.

Aliquot vessel array transport system 50 comprises an aliquot vesselarray storage and dispense module 56 and a number of linear drive motors58 adapted to bi-directionally translate aliquot vessel arrays 52 withina number of aliquot vessel array tracks 57 below a sample aspiration anddispense arm 54 located proximate reaction carousel 12. Sampleaspiration and dispense arm 54 is controlled by computer 15 and isadapted to aspirate a controlled amount of sample from individualvessels or wells 52W positioned at a sampling location within a track 57using a conventional liquid probe 54P and then liquid probe 54P isshuttled to a dispensing location where an appropriate amount ofaspirated sample is dispensed into one or more cuvettes 24 in cuvetteports 20 for testing by analyzer 10 for one or more analytes. Aftersample has been dispensed into reaction cuvettes 24, conventionaltransfer means move aliquot vessel arrays 52 as required between aliquotvessel array transport system 50, environmental chamber 38 and adisposal area, not shown.

A number of reagent aspiration and dispense arms 60, 61 and 62comprising conventional liquid reagent probes, 60P, 61P and 62P,respectively, are independently mounted and translatable between reagentstorage areas 26, 27 and 28, respectively and outer cuvette carousel 14.Probes 60P and 62P comprise conventional mechanisms for aspiratingreagents required to conduct specified assays at a reagenting locationfrom wells 32 in an appropriate reagent cartridge 30, the probes 60P,61P and 62P subsequently being shuttled to a reagent dispensing locationwhere reagent(s) are dispensed into reaction cuvettes 24 contained incuvette ports 20 in outer cuvette carousel 14. Additional probes may beprovided to provide increased flexibility if desired. A number ofreagent cartridges 30 are inventoried in controlled environmentalconditions inside reagent storage areas 26, 27 and 28; a key factor inmaintaining high assay throughput of analyzer 10 is the capability toinventory a large variety of reagent cartridges 30 inside reagentstorage areas 26A and 26B, 27 and 28 and to then quickly transfer randomones of these reagent cartridges 30 to reagenting locations for accessby probes 60P, 61P and 62P.

Reaction cuvette load station 63 and reaction vessel load station 65 arerespectively positioned proximate outer cuvette carousel 14 and innervessel carousel 16 and are adapted to load reaction cuvettes 24 intocuvette ports 20 sideways as described later and reaction vessels 25into vessel ports 22 using for example a translatable robotic arm 67. Inoperation, used cuvettes 24 in which an assay has been finallyconducted, are washed and dried in a wash station 71 like disclosed inco-pending application Ser. No. 10/623,360 assigned to the assignee ofthe present invention. Subsequent assays are conducted in cleaned usedcuvettes 24 unless dictated otherwise for reasons like disclosed inco-pending application Ser. No. 10/318,804 assigned to the assignee ofthe present invention. Cuvette unload station 59 is adapted to removeunusable reaction cuvettes 24 from cuvette ports 20 again using atranslatable robotic arm 67 like seen on load stations 63 and 65.

FIG. 6 illustrates a single, bi-directional linear reagent containershuttle 72 adapted to remove reagent containers 30 from reagentcontainer loading tray 29 having a motorized rake 73 that automaticallylocates containers 30 at a loading position beneath reagent containershuttle 72. Reagent containers 30 are identified by the type of assaychemicals contained in wells 32 using conventional barcode-like indiciaand a bar-code-reader 41 proximate reagent container loading tray 29.Computer 15 is programmed to track the location of each and everyreagent container 30 as it is transported within analyzer 10. Shuttle 72is further adapted to dispose a reagent container 30 into slots in atleast one slotted reagent container tray 27T or 28T within at least onereagent storage area 27 or 28, respectively. In a similar fashion,shuttle 72 is further adapted to remove reagent containers 30 fromreagent container trays 27T and 28T and to dispose such reagentcontainers 30 into either of two concentric reagent carousels 26A and26B within reagent storage area 26. Shuttle 72 is also adapted to movereagent containers 30 between the two concentric reagent carousels 26Aand 26B. As indicated by the double-headed arc-shaped arrows, reagentcarousel 26A may be rotated in both directions so as to place anyparticular one of the reagent containers 30 disposed thereon beneathreagent aspiration arm 60. Although reagent carousel 26B may alsocontain reagent containers 30 accessible by reagent aspiration arm 60,carousel 26B may be designated only for storing excess inventory ofreagent containers 30 and vial containers 30A having calibration orquality control solutions therein. Any one of the reagent containers 30disposed in reagent container trays 27T and 28T may be located at aloading position beneath reagent container shuttle 72 or at a reagentaspiration location beneath aspiration and dispensing arms 61 and 62,respectively, by reagent container shuttles 27S and 28S within reagentstorage areas 27 and 28, respectively. Hereinafter, the term “server” ismeant to define the combination of either reagent container shuttle 27Sor 28S and either reagent storage area 27 or 28 and either reagentcontainer tray 27T or 28T, respectively. Reagent container shuttles 27Sand 28S are similar in design to reagent container shuttle 72. Reagentaspiration arms 60, 61 and 62 are shown in dashed lines to indicate thatthey are positioned above the surfaces of reagent containers 30inventoried in carousel 26B, and reagent container trays 27T and 28T,respectively. Reaction cuvettes 24 supported in outer cuvette carousel14 are also both shown in dashed lines to indicate that they arepositioned above the surfaces of reagent containers 30.

From the foregoing description, it is clear that shuttle 72 may movereagent containers 30 between reagent container loading tray 29, reagentcontainer trays 27T and 28T, and reagent carousels 26A and 26B; further,shuttles 27S and 28S may move reagent containers 30 in reagent containertrays 27T and 28T to appropriate aspiration locations (or to a loadinglocation beneath shuttle 72) and reagent carousels 26A and 26B may placeany reagent container 30 beneath reagent aspiration arm 60. Analyzer 10is thus equipped with a random access reagent supply system with theflexibility to position a large number of different reagent containers30 at different aspiration locations. Shuttles 72, 27S and 28S areequipped with automatic tension controls like disclosed in co-pendingapplication Ser. No. 10/623,311 assigned to the assignee of the presentinvention so that the time required for reagent supply in analyzer 10 isnot a throughput limitation.

In operation of analyzer 10, and in accord with the present invention,analyzer 10 is operated in a manner that achieves high throughputirregardless of the incoming demand for assays, or assay load mix, ofdifferent assays required to be conducted for different samplespresented to analyzer 10. For the purpose of further explanation,consider an exemplary embodiment of the present invention in whichreaction carousel 12 comprises 184 cuvette ports 24 located in cuvettering 14 and moves or advances step-wise in a single rotational direction(clockwise or counter-clockwise) a total of 77 cuvette positions duringeach machine cycle. Each step-wise movement of 77 cuvette positions isfollowed by a corresponding stationary dwell time. The combination of astep-wise movement and subsequent stationary dwell time comprise amachine cycle of 3.6 seconds and are equal in time, so that reactioncarousel 12 moves step-wise for a total of 1.8 seconds and issubsequently stationary for a period of 1.8 seconds. The prime-numberrelationships between the numbers of 184 cuvette ports 72 and the numberof 77 cuvette positions moved in each machine cycle is well known in theart (U.S. Pat. No. 5,352,612) from which it may be determined that aftera total of 184 machine cycles occur, each and every cuvette port 24 isreturned to its each and every original starting position, therebydefining a full carousel cycle of 184 machine cycles of duration 3.6seconds; the full operational cycle time of carousel 12 thus comprises662.4 seconds or approximately 11 minutes. It should be emphasized thatthe values used in this exemplary example are not restrictive and thatthe principles of the present invention may be applied to any similarlyoperable analyzer 10. It is only required that each and every cuvetteport 24 is returned to its each and every original starting position ina constant amount of time.

It is known that throughput of analyzer 10 may be increased bypartitioning of the assays to be performed into groups defined by thelength of time required to complete those assays, as disclosed in U.S.patent application Ser. No. 09/917,132. To achieve these ends, liquidaspiration and dispense arm 60 located proximate reagent storage areas26 is controlled by CPU 15, according to pre-programmed software,firmware, or hardware commands or circuits to remove reagent fromcartridges 30 stored within reagent storage area 26 and to dispenseaspirated reagent into cuvettes 24 for a first grouping of assays calledType C assays, Type C assays comprising all assays having multiplereagent events or for which final incubation and test readings arecompleted in an amount of time greater than one-half the fulloperational cycle time of carousel 12. Assuming the exemplaryoperational cycle time of carousel 12 as described above, analyzer 10 iscapable of performing about 350 Type C assays per hour.

Aspiration and dispense arm 61 is similarly operable to remove reagentsfrom cartridges 30 stored within reagent storage area 27 and to dispenseaspirated reagent into cuvettes 24 for a second smaller grouping offewer assays called Type B assays, Type B assays comprising all assayshaving two reagent events and for which final incubation and testreadings can be completed by the analyzer in an amount of time less thanabout one-half the full operational cycle time of carousel 12. Assumingthe operational cycle time of carousel 12 as described above, analyzer10 is capable of performing about 500 Type B assays per hour.

Aspiration and dispense arm 62 is similarly operable to remove reagentsfrom cartridges 30 stored within reagent storage area 28 and to dispenseaspirated reagent into cuvettes 24 for a third smaller grouping of fewerassays called Type A assays, Type A assays comprising all assays havinga single reagent event and for which final incubation and test readingscan be completed by the analyzer in an amount of time less than aboutone-third the full operational cycle time of carousel 12. Assuming theexemplary operational cycle time of carousel 12 as described above,analyzer 10 is capable of performing about 500 Type A assays per hour.

FIG. 7 illustrates the aforementioned partitioning of assays capable ofbeing performed by analyzer 10 into three time-dependentassay-categories. As a matter of convention, time t=0.0 seconds isdefined as the moment of sample dispensing into a test cuvette 19; forthe sake of simplicity, all three types of assays are shown as having asingle reagent addition R1 at a fixed time before sample addition. FIG.7 shows how Type A assays comprise an assay format having a singlereagent event and a final reading, indicated by Rf, completed withinabout 130-140 seconds after sample addition. Similarly, Type B assayscomprise an assay format having two reagent events and a final readingcompleted within about 330-350 seconds after sample addition. Finally,Type C assays comprise an assay format having at least one reagent evenand a final reading completed within between about 350 and 560 secondsafter sample addition. At any time, indicated by Rd, during the assays,a reaction vessel reading or analysis may be made by any of the devices70.

Table 1 contains a limited but illustrative listing of typical clinicaland immunoassays for various Type A, B and C analytes along with timingdetails for various reagent additions and device operations.

TABLE 1 Assay TYPE R1/T1 S R2/T2 Rx/Tx Rd1 Rd2 Rf-Final Albumin A −21.60.0 n/a 124.7 Alkaline Phosphatase B −21.6 0.0 220 284.5 342.1 Ammonia C−21.6 0.0 205.6 241.3 450.1 Blood Urea Nitrogen A −21.6 0.0 n/a 124.7Calcium A −21.6 0.0 n/a −27.9 67.1 Cholesterol (HDL) C −21.6 0.0 147.5141.1 442.9 Cholesterol (Total) A −21.6 0.0 n/a 378.1 C-Reactive ProteinB −21.6 0.0 N/a −22.3 31.1 228.3 Complement 3 C −21.6 0.0 220 44.1 189.5430.1 Creatine Kinase B −21.6 0.0 n/a 226.9 284.5 Creatinine A −21.6 0.0n/a 29.7 59.9 Digitoxin C −21.6 0.0 248.0 426.9 450.0 Direct Bilirubin B−21.6 0.0 220 182.3 277.3 Gamma Glutamyl Transferase A −21.6 0.0 n/a110.3 Gentamicin B −21.6 0.0 175.3 44.9 58.9 359.9 Glucose A −21.6 0.0n/a −27.9 103.1 178.3 Lactate Dehydrogenase A −21.6 0.0 n/a 124.7 LacticAcid C −21.6 0.0 68.8 36.9 658.9 Methadone A −21.6 0.0 119 150.9 179.7Phenobarbital C −21.6 0.0 220 29.7 182.3 442.9 Phenytoin B −21.6 0.067.4 44.1 255.7 Phosphorous B −21.6 0.0 220 182.3 342.1 Prealbumin B−21.6 0.0 −17.3 29.9 297.9 Prostatic Acid Phosphatase C −21.6 0.0 463.6514.9 Pseudocholinesterase B −21.6 0.0 220 255.7 284.5 Salicylate A−21.6 0.0 54.4 36.9 88.7 Total Bilirubin C −21.6 0.0 220 182.3 342.1450.1 Total CO2 A −21.6 0.0 n/a −40.9 20 59.9 Transferrin C −21.6 0.0220 44.1 189.5 430.1 Triglyceride B −21.6 0.0 220 255.7 284.5 ValproicAcid C −21.6 0.0 n/a 74.9 212.9 422.8

An example of analyzer 10 operating in a manner to advantageouslyperform the three assay type A, B, and C follows. Prior to the loadingof a cuvette 24 with sample contained within aliquot wells 52W and to betested using a Type A assay, a first reagent R1 is aspirated by arm 62from an appropriate compartment of a reagent cartridge 30 within reagentstorage area 28 and is deposited into a cuvette 24A within a cuvetteport 21 at a time T1. At time T0, samples for which Type A assays are tobe conducted are aspirated by probe 54P and deposited within the cuvette24A preloaded with reagent R1.

In a similar manner, prior to the loading of a cuvette 24B with samplecontained within aliquot wells 52W and to be tested using a Type Bassay, a first reagent R1 is aspirated by arm 61 from an appropriatecompartment of a reagent cartridge 24 within reagent storage area 27 andis deposited into cuvette 24B within a cuvette port 21 at a time T1. Attime T0, samples for which Type B assays are to be conducted areaspirated by probe 54P and deposited within cuvette 24B. As mentionedabove, in the instance of Type B assays, a second reagent addition maybe accomplished at a time T2 after T0, again using arm 61 to access areagent cartridge 30 within reagent storage area 27.

Finally, prior to the loading of a cuvette 24C with sample containedwithin aliquot wells 52W and to be tested using a Type C assay, a firstreagent R1 is aspirated by arm 60 from an appropriate compartment of areagent cartridge 24 within reagent storage area 26 and is depositedinto cuvette 24C within a cuvette port 20 or 22 at a time T1. At timeT0, samples for which Type C assays are to be conducted are aspirated byprobe 54P and deposited within cuvette 24B. As mentioned above, in theinstance of Type C assays, a second reagent or third addition may beaccomplished at a time T2 after T0 and a time Tx before or after T0,again using arm 60 to access a reagent cartridge 24 within reagentstorage area 26.

After the cuvettes 24 are loaded with the just described reagents andsamples, reaction carousel 12 continues its stepwise clockwise movementduring which machine cycles, assay operational devices 34 operate uponthe mixture within the cuvettes 24 in cuvette ports 20, 21 and 22according to the appropriate assay protocols.

Because Type B assays have been partitioned in a manner such that allsuch assays are completed in less than one-half of the time required forreaction carousel 12 to complete a full operational cycle time, cuvettes24B containing completed Type B assays may washed in the outer cuvettecircle 14 of the reaction carousel 12 by wash station 71 and madeavailable for a second Type B assay or for a Type A assay, depending onthe mixture of assay types required to be performed by analyzer 10.Cuvette ports 21 are marked “B/A” or “B/B” to signify this scheme.Reaction carousel 12 continues its stepwise clockwise movement, duringwhich machine cycles conventional assay operational devices 34 operateupon the mixture within the cuvettes 24A containing Type A assays and incuvettes 24C containing Type C assays according to the appropriate assayprotocols until the reaction carousel 12 completes a complete a fulloperational cycle time and both the Type A assays and Type C assays arecompleted.

In comparison with conventional analyzers in which completed Type Bassays would remain on reaction carousel 12 for a full operational cycletime and hinder analyzer throughput, this alternate processing method inwhich one medium time length assay, described as a Type B assay, and oneshorter time length assay, described as a Type A assay, are bothcompleted during the same operational cycle time as required for onelonger time length assay, described as a Type C assay, is completed,thereby enhancing throughput of analyzer 10.

It has been found, however, that typical health care facilitiesexperience a first demand pattern at the beginning of a day and adifferent second demand pattern towards the middle of a day. FIG. 8illustrates the rate of incoming patient samples having assays to beconducted over a full 24-hour day. These are generally the two peak loadperiods within a day and while the numerical demand for assays is aboutthe same, the pattern of assays requested is different. Actualexperience at a “high volume” laboratory is illustrated in Table IIbelow which shows that the percentage of Type C assays increasessignificantly but at the same time, the percentage of Type A assaysdecreases significantly. The “routine morning” mix of assays comprises83 samples having a distribution of assays like shown in Table II.

TABLE 2 Type C Type B Type A AM Morning Assay 17% 15% 68% Demand PatternPM Afternoon Assay 35% 19% 46% Demand Pattern Relative +106% +27% −32%Change

It is clearly not advantageous with achieving high throughputirregardless of the mix of different assays required to be conducted tomaintain a single assay operating protocol for analyzer 10. Inparticular, using a “morning-optimized” operating protocol defined abovein the first example using the AM column of assay demand in Table 2, thethroughput of analyzer 10 during the PM afternoon hours would then bereduced.

A key feature of the present invention is the discovery that if thereagent resources required to conduct a small number of selected highvolume “routine morning” Type A assays are duplicated in more than oneof the reagent servers 26, 27, or 28, then it is possible to optimizethe throughput of “routine morning” assays at the beginning of a day aswell as the throughput of “esoteric afternoon” assays hours later inthat day. Thus, in addition to partitioning of assays into Type A, TypeB or Type C assays so that multiple Type A and/or Type B assays may befully performed during a single full operational cycle time, the presentinvention also adds reagents as necessary to perform selected Type Aassays into the inventory of reagents into at least reagent server 26,previously reserved for Type C assays, and optionally also into reagentserver 27, previously reserved for Type B assays.

The present invention is practiced by initially identifying an“non-optimized” assay operating protocol like illustrated in FIG. 9 inwhich a subgroup of the high volume “routine morning” Type A assays isdefined such that as many as possible of the reagents required forconducting such assays at the Afternoon Assay Demand Pattern aresupplied from reagent server 28. In addition, a subgroup of Type Bassays is defined such that as many as possible of the reagents requiredfor conducting such assays at the Afternoon Assay Demand Pattern aresupplied from reagent server 27. In this scheme, third reagent server 26supplies reagents required for conducting a remaining third group ofassays, wherein the first, second and third groups of assays compriseall assays analyzer 10 is equipped to conduct.

Subsequently, the throughput of analyzer 10 is optimized for bothmorning and afternoon assay demand patterns by duplicating within theinventory of reagents in reagent server 26 those additional reagentsrequired for conducting the subgroup of high volume “routine morning”Type A assays at the Morning Assay Demand Pattern as illustrated in FIG.9A. These certain assays (shared across servers) are selected fromwithin the first subgroup of assays. This duplication of reagents isindicated in FIG. 9A by vertical dashed line 71 and the term “Server 26”in italics. Optionally, a selected portion of the reagents required forconducting the first subgroup of high volume “routine morning” Type Aassays at the Morning Assay Demand Pattern may optionally also beduplicated within the inventory of reagents in reagent server 27 asindicated by vertical dashed line 73 and the term “Server 27” initalics. This novel reagent sharing protocol significantly enhancesanalyzer throughput since a sufficient quantity of the reagents requiredfor conducting high volume “routine morning” Type A assays at theMorning Assay Demand Pattern is available on analyzer 10 so that nobacklog of Type A assays exists during AM time period. It should benoted that server 26 is initially loaded or inventoried with asufficient quantity of the reagents required for conducting Type Cassays at the Afternoon Assay Demand Pattern and since the Morning AssayDemand Pattern for Type C assays is lower for such assays, server 26 hassufficient capacity to inventory both the additional reagents requiredfor conducting the first subgroup of high volume “routine morning” TypeA assays at the Morning Assay Demand Pattern as well as the reagentsrequired for conducting Type C assays at the Afternoon Assay DemandPattern. Consequently, analyzer 10 may be automatically operated by CPU15 such that newly incoming Type A assays within the sub-group of highvolume “routine morning” Type A assays are conducted using reagents fromwhichever reagent server 26, 27 or 28 has the smaller backlog ofpreviously assigned assays from within said high volume “routinemorning” Type A assays.

As an illustration of the advantages of such an assay operatingprotocol, consider a typical health care facility having a morninghourly demand rate for “routine morning” assays depicted as AM andhaving a “esoteric afternoon” hourly demand rate for assays depicted asPM in Table 3, and having the associated assay format types in analyzer10. In this first example, corresponding to FIG. 8, in which thethroughput of analyzer 10 will be optimized for the AM columnrepresentative of the hourly demand for “routine morning” assays, theadditive hourly demand for a first group of Type A assays comprisesTotal CO₂ (185/hr) and Glucose (170) and Creatinin (120) and Blood UreaNitrogen (106) and Calcium (105) totals 686 Type A assays per hour whichexceeds the 500 assay/hour capacity of analyzer 10 for Type A assays forthe particular embodiment of analyzer 10 described above with reagentsfor Type A assays supplied from server 28. Consequently, during themorning time frame, analyzer 10 will have a backlog of 168 Type A assaysper hour for these high demand assays.

In this non-optimum scenario, and during the same during the morningtime frame, the additive hourly demand for Type B assays comprisesAlkaline Phosphatase (55) and Triglyceride (45) and Phosphorous (28) andDirect Bilirubin (30) and C-Reactive Protein (8) and Creatine Kinase (5)and Gentamicin (5) and Phenytoin (3) and Pseudocholinesterase (0) whichtotals 151 Type B assays well within the capacity of analyzer 10 for theparticular embodiment described above as about 500 Type B assays perhour.

Also, in this non-optimum scenario, and during the same during themorning time frame, the additive hourly demand for Type C assayscomprises Total Bilirubin (74) and HDL Cholesterol (33) and Digitoxin(9) and Lactic Acid (3) and Prostatic Acid Phosphatase (3) and Ammonia(3) and Valproic Acid (3) and Transferrin (2) and Complement 3 (2) whichtotals 132 Type C assays per hour. Since server 26 (1) is initiallyinventoried with the reagents required for conducting Type C assays atthe Afternoon Assay Demand Pattern which has an additive hourly demandfor Type C assays comprising Total Bilirubin (152) and HDL Cholesterol(66) and Digitoxin (18) and Lactic Acid (6) and Prostatic AcidPhosphatase (6) and Ammonia (6) and Valproic Acid (6) and Transferrin(4) and Complement 3 (4) which totals 286 Type C assays per hour, thenserver 26 (1) is not fully utilized during the morning time frame as theanalyzer 10 is capable of performing about 350 Type C assays per hourwhile the additive hourly demand for Type A and Type C assays totals 632assays per hour while the capacity for performing Type A and Type Cassays totals 850 assays per hour.

TABLE 3 AM Hourly PM Hourly Assay Type Demand Demand Albumin A 41 28Alkaline Phosphatase B 55 70 Ammonia C 3 6 Blood Urea Nitrogen A 106 72Calcium A 105 71 HDL Cholesterol C 33 66 (Total) Cholesterol A 38 26C-Reactive Protein B 8 10 Complement 3 C 2 4 Creatine Kinase B 5 6Creatinine A 120 105 Digitoxin C 9 18 Direct Bilirubin B 30 38 GammaGlutamyl Transferase A 35 24 Gentamicin B 5 6 Glucose A 170 116 LactateDehydrogenase A 22 15 Lactic Acid C 3 6 Methadone A 2 1 Phenobarbital C2 4 Phenytoin B 3 4 Phosphorous B 28 36 Prealbumin B 3 4 Prostatic AcidPhosphatase C 3 6 Pseudocholinesterase B 0 15 Total Bilirubin C 74 152Total CO₂ A 185 126 Salicylate A 2 1 Transferrin C 2 4 Triglyceride B 4557 Valproic Acid C 3 6

In contrast with the above and as depicted in FIG. 8A and Table 4, andas provided for by the present invention, server 26 will also inventorythe reagents required to perform 168 high demand Type A assays per hour.In terms of this example of a typical health care facility, the totalhourly capacity for “routine morning” assays to be conducted by analyzer10 is optimized as

-   -   500 assays per hour for Type A assays from server 28;    -   168 assays per hour for Type A assays from server 26;    -   151 assays per hour for the Type B assays from server 27; and,    -   286 assays per hour for Type C assays from server 26,        so that the total capacity of analyzer 10 is 1105 “routine        morning” assays/hour.

During the Afternoon Assay Demand Pattern times, the additive hourlydemand for Type A assays decreases as seen in Table 2 and comprisesTotal CO₂ (126/hr) and Glucose (116) and Creatinin (105) and Blood UreaNitrogen (72) and Calcium (71) totals 490 Type A assays per hour whichis within the 500 assay/hour capacity of analyzer 10 for Type A assaysfor the particular embodiment of analyzer 10 described above withreagents for Type A assays supplied from server 28. Consequently, duringthe afternoon time frame, analyzer 10 will not have a backlog of Type Aassays.

During the same afternoon time frame, the additive hourly demand forType B assays comprises Alkaline Phosphatase (70) and Triglyceride (57)and Phosphorous (36) and Direct Bilirubin (38) and C-Reactive Protein(10) and Creatine Kinase (6) and Gentamicin (6) and Phenytoin (4) andPseudocholinesterase (15) which totals 242 Type B assays well within thecapacity of analyzer 10 for the particular embodiment described above asabout 500 Type B assays per hour.

Similarly, during the same afternoon time frame and as explainedpreviously, the additive hourly demand for Type C assays comprises TotalBilirubin (152) and HDL Cholesterol (66) and Digitoxin (18) and LacticAcid (6) and Prostatic Acid Phosphatase (6) and Ammonia (6) and ValproicAcid (6) and Transferrin (4) and Complement 3 (4) which totals 268 TypeC assays per hour. Since server 26 (1) is initially inventoried with thereagents required for conducting Type C assays at the Afternoon AssayDemand Pattern, then server 26 is capable of performing all requiredType C assays.

In terms of this example of a typical health care facility in which thetotal hourly capacity of analyzer 10 is optimized as seen by identifyingcertain exemplary Type A assays in Table 4 for both morning andafternoon assay demand patterns by duplicating within the inventory ofreagents in reagent server 26 those additional reagents required forconducting a subgroup of high volume “routine morning” Type A assays,then the throughput of “esoteric afternoon” assays becomes:

-   -   490 assays/hour for Type A assays;    -   242 assays/hour for Type B assays; and,    -   268 assays per hour for Type C assays,

so that the capacity of analyzer 10 is 1000 assays per hour in theafternoon time frame compared to the 1105 assays/hour in the morningtime frame. In other words, the throughput of analyzer 10 may beoptimized for both morning and afternoon assay demand patterns byduplicating within the inventory of reagents in reagent server 26 thoseadditional reagents required for conducting a subgroup of high volume“routine morning” Type A assays within the Morning Assay Demand Pattern.

TABLE 4 AM PM Hourly Hourly “Original” “Optimized” Assay Type DemandDemand Server Server(s) Blood Urea A 106 72 28 (3) 28 (3) NitrogenCalcium A 105 71 28 (3) 28 (3) Creatinine A 120 105 28 (3) 28 (3) TotalCO₂ A 185 126 28 (3) 26 (1) and 28 (3) Glucose A 170 116 28 (3) 26 (1)and 28 (3)

Furthermore, a key feature of the present invention is the additionaladvantage that analyzer 10 may be operated by CPU 15 so that for everynewly incoming selected Type A assay having the required reagents inboth of reagent servers 26 and 28, new patient samples may be assayedusing reagents from whichever of the two reagent servers 26 and 28 hasthe shortest demand backlog, thereby improving the individual assaythroughput times required for these selected Type A assays to becompleted.

The details of performing a myriad of assays like those in Tables 1 and3 within a clinical analyzer is a task regularly encountered within theart and need not be described herein. It is sufficient that theteachings of the present invention, that overall analyzer throughput maybe improved by enabling certain selected assays to be conducted usingreagents from at least two servers. It is further obvious to one skilledin the art that the above described method for operating a clinicalanalyzer so as to simultaneously increase throughput regardless ofwhether the incoming assay demand pattern has a larger portion of afirst group of assays or a larger portion of a second group of assays inaddition to enabling certain selected assays to be conducted usingreagents from whichever of at least two servers has the shorter backlogof demand is not dependent upon the specific operating parameters ofanalyzer 10 in the examples above. For example, analyzer 10 may have adifferent arrangement of cuvette ports 20 and 21 that return to theiroriginal location in a full operational cycle time, a differentoperating pattern for reaction carousel 12, different assay throughputs,sample and reagent aspiration and dispense arms and the like withoutaffecting the operational method disclosed herein. For these reasons,the present invention is not limited to those embodiments preciselyshown and described in the specification but only by the followingclaims.

1. A method for increasing the throughput of an analyzer equipped for conducting a number of different assays on a clinical sample, the method comprising the steps of: (a) providing a source of samples to be assayed by the analyzer; (b) providing a reaction carousel having reaction cuvettes for containing the samples to be assayed; (c) providing first, second, and third sources of reagents for conducting reactions on the samples in the reaction cuvettes; and (d) partitioning the different assays to be conducted by the analyzer into (i) a first sub-group of assays consisting only of those assays having the highest frequency of being conducted by the analyzer; (ii) a third sub-group of assays consisting only of those assays having the lowest frequency of being conducted by the analyzer; and (iii) a second sub-group of assays consisting only of those assays not contained in either the first or third sub-groups of assays, wherein the first third source of reagents contains reagents needed for conducting the first, second, and third sub-groups of assays, the second source of reagents consists only of those reagents needed for conducting the first and second sub-groups of assays, and the third first source of reagents consists only of those reagents needed for conducting the first sub-group of assays.
 2. The method of claim 1 further comprising selecting reagents from whichever of the three servers has the shortest backlog of demand with which to perform assays in the first sub-group of assays. 